Pyrrolo[2,3-d]pyrimidine compounds

ABSTRACT

A compound of the formula 
                         
wherein R 1 , R 2  and R 3  are as defined above, which are inhibitors of the enzyme protein kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn&#39;s disease, Alzheimer&#39;s disease, Leukemia and other autoimmune diseases.

This application is a continuation of U.S. Patent Application No.11/211,217 filed Aug. 24, 2005, now issued as U.S. Pat. No. 7,091,208,which is a divisional of U.S. patent application Ser. No. 10/640,227filed Aug. 13, 2003, now issued as U.S. Pat. No. 6,956,041, which inturn is a continuation of U.S. patent application Ser. No. 09/732,669filed Dec. 8, 2000, now issued as U.S. Pat. No. 6,627,754, which in turnclaims the benefit of priority under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 60/170,179 filed Dec. 10, 1999, allof which are hereby incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION

The present invention relates to pyrrolo[2,3]pyrimidine compounds whichare inhibitors of protein kinases, such as the enzyme. Janus Kinase 3(hereinafter also referred to as JAK3) and as such are useful therapy asimmunosuppressive agents for organ transplants, xeno transplation,lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type Idiabetes and complications from diabetes, cancer, asthma, atopicdermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn'sdisease, Alzheimer's disease, Leukemia and other indications whereimmunosuppression would be desirable.

This invention also relates to a method of using such compounds in thetreatment of the above indications in mammals, especially humans, andthe pharmaceutical compositions useful therefor. JAK3 is a member of theJanus family of protein kinases. Although the other members of thisfamily are expressed by essentially all tissues, JAK3 expression islimited to hematopoetic cells. This is consistent with its essentialrole in signaling through the receptors for IL-2, IL-4, IL-7, IL-9 andIL-15 by non-covalent association of JAK3 with the gamma chain common tothese multichain receptors. XSCID patient populations have beenidentified with severely reduced levels of JAK3 protein or with geneticdefects to the common gamma chain, suggesting that immunosuppressionshould result from blocking signaling through the JAK3 pathway. Animalstudies have suggested that JAK3 not only plays a critical role in B andT lymphocyte maturation, but that JAK3 is constitutively required tomaintain T cell function. Modulation of immune activity through thisnovel mechanism can prove useful in the treatment of T cellproliferative disorders such as transplant rejection and autoimmunediseases.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

R¹ is a group of the formula

wherein y is 0, 1 or 2;

R⁴ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl wherein the alkyl,alkenyl and alkynyl groups are optionally substituted by deuterium,hydroxy, amino, trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, nitro, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴ is (C₃-C₁₀)cycloalkyl whereinthe cycloalkyl group is optionally substituted by deuterium, hydroxy,amino, trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino;

R⁵ is (C₂-C₉)heterocycloalkyl wherein the heterocycloalkyl groups mustbe substituted by one to five carboxy, cyano, amino, deuterium, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R⁶NS(O)_(m) (C₁-C₆)alkyl,R¹⁵S(O)_(m) R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁵ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein a is 0, 1, 2, 3 or 4;b, c, e, f and g are each independently 0 or 1;d is 0, 1, 2, or 3;X is S(O)_(n) wherein n is 0, 1 or 2; oxygen, carbonyl or —C(═N-cyano)—;Y is S(O)_(n) wherein n is 0, 1 or 2; or carbonyl; andZ is carbonyl, C(O)O—, C(O)NR— or S(O)_(n) wherein n is 0, 1 or 2;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from thegroup consisting of hydrogen or (C₁-C₆)alkyl optionally substituted bydeuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino;

R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl,(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,(C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂ amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₁-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl;

R² and R³ are each independently selected from the group consisting ofhydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substituted by one to threegroups selected from halo, hydroxy, carboxy, amino(C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl, (C₆-C₁₀)arylaminoCO—NH—(C₁-C₆)alkyl, (C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl,(C₆-C₁₀)arylsulfonylamino, (C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₅-C₉)heteroaryl or (C₂-C₉)heterocycloalkyl.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties or combinations thereof.

The term “alkoxy”, as used herein, includes O-alkyl groups wherein“alkyl” is defined above.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo.

The compounds of this invention may contain double bonds. When suchbonds are present, the compounds of the invention exist as cis and transconfigurations and as mixtures thereof.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(alkoxy), may be linear or branched, and they may also be cyclic (e,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or belinear or branched and contain cyclic moieties. Unless otherwiseindicated, halogen includes fluorine, chlorine, bromine, and iodine.

(C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl;1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

(C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl,pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl,tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

(C₆-C₁₀)aryl when used herein refers to phenyl or naphthyl.

Compounds of formula (I) may be administered in a pharmaceuticallyacceptable form either alone or in combination with one or moreadditional agents which modulate a mammalian immune system or withantiinflammatory agents. These agents may include but are not limited tocyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®), azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®. OKT3(e.g. Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen,piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone). These agents may be administered as part of the same orseparate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

The compounds of this invention include all conformational isomers(e.g., cis and trans isomers. The compounds of the present inventionhave asymmetric centers and therefore exist in different enantiomericand diastereomeric forms. This invention relates to the use of alloptical isomers and stereoisomers of the compounds of the presentinvention, and mixtures thereof, and to all pharmaceutical compositionsand methods of treatment that may employ or contain them. In thisregard, the invention includes both the E and Z configurations. Thecompounds of formula I may also exist as tautomers. This inventionrelates to the use of all such tautomers and mixtures thereof.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula I. This invention also encompassesmethods of treating or preventing disorders that can be treated orprevented by the inhibition of protein kinases, such as the enzyme JanusKinase 3 comprising administering prodrugs of compounds of the formulaI. Compounds of formula I having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy orcarboxylic acid groups of compounds of formula I. The amino acidresidues include the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin,beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,homoserine, ornithine and methioine sulfone. Prodrugs also includecompounds wherein carbonates, carbamates, amides and alkyl esters whichare covalently bonded to the above substituents of formula I through thecarbonyl carbon prodrug sidechain.

Preferred compounds of formula I include those wherein a is 0; b is 1; Xis carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0, and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is —C(═N=cyano)-; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is —C(O)—O—.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); n is 2; c is 0; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; andZ is carbonyl.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); n is 2; c is 0; d is 2; e is 0; f is 1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 1; d is 0; e is 1; Y is S(O)_(n); n is 2; f is0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); is 2; c is 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 1; bis 1; X is carbonyl; cis 1; d is 0; e is 0; f is 0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); c is 6; d is 1; e is 1; Y is S(O)_(n); n is 2; f is0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is S(O)_(n); c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; f is1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; f is1; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; f is0; and g is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)_(n); f is 0; andg is 0.

Other preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)_(n); n is 2; f is1; and g is 0.

Other preferred compounds of formula I include those wherein R¹² iscyano, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkynyl,cyano(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m) wherein m is 0, 1 or 2.

Specific preferred compounds of formula I include those wherein saidcompound is selected from the group consisting of:

Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methyl ester;

3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;

4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]piperidine-1-carboxylicacid dimethylamide;

({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-aceticacid ethyl ester;

3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile;

3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;

1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yl-1-one;

1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;

1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;

N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-N′-propyl-piperidine-1-carboxamidine;and

N-cyano-4,N′,N′-Trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-amino]-piperidine-1-carboxamidine.

The present invention also relates to a pharmaceutical composition for(a) treating or preventing a disorder or condition selected from organtransplant rejection, xeno transplation, lupus, multiple sclerosis,rheumatoid arthritis, psoriasis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, Crohn's disease, Alzheimer's disease,Leukemia, and other autoimmune diseases or (b) the inhibition of proteinkinases or Janus Kinase 3 (JAK3) in a mammal, including a human,comprising an amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof, effective in such disorders or conditions and apharmaceutically acceptable carrier.

The present invention also relates to a method for the inhibition ofprotein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising administering to said mammal an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, andother autoimmune diseases in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of formula I or apharmaceutically acceptable salt thereof, effective in treating such acondition.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R², R³,R⁴ and R⁵ in the reaction Schemes and the discussion that follow aredefined as above.

In reaction 1 of Preparation A, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XXI, wherein R is hydrogen or a protecting groupsuch as benzenesulfonyl or benzyl, is converted to the4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, whereinY is chloro, bromo or iodo, by reacting XXI with N-chlorosuccinimide,N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heatedto reflux, in chloroform, for a time period between about 1 hour toabout 3 hours, preferably about 1 hour. Alternatively, in reaction 1 ofPreparation A, the 4-chloropyrrolo[2,3-d]pyrimidine of formula XXI,wherein R is hydrogen, is converted to the corresponding4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y isnitro, by reacting XXI with nitric acid in sulfuric acid at atemperature between about −10° C. to about 10° C., preferably about 0°C., for a time period between about 5 minutes to about 15 minutes,preferably about 10 minutes. The compound of formula XXI, wherein Y isnitro, is converted to the corresponding4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the formula XX, wherein Y isamino, by reacting XXI under a variety of conditions known to oneskilled in the art such as palladium hydrogenolysis or tin(IV)chlorideand hydrochloric acid.

In reaction 2 of Preparation A, the4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, whereinR is hydrogen, is converted to the corresponding compound of formulaXIX, wherein R² is (C₁-C₆)alkyl or benzyl, by treating XX withN-butyllithium, at a temperature of about −78° C., and reacting thedianion intermediate so formed with an alkylhalide or benzylhalide at atemperature between about −78° C. to room temperature, preferably roomtemperature. Alternatively, the dianion so formed is reacted withmolecular oxygen to form the corresponding4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX,wherein R² is hydroxy. The compound of formula XX, wherein Y is bromineor iodine and R is benzenesulfonate, is converted to the compound offormula XIX, wherein R² is (C₆-C₁₂)aryl or vinyl, by treating XX withN-butyllithium, at a temperature of about −78° C., followed by theaddition of zinc chloride, at a temperature of about −78° C. Thecorresponding organo zinc intermediate so formed is then reacted witharyliodide or vinyl iodide in the presence of a catalytic quantity ofpalladium. The reaction mixture is stirred at a temperature betweenabout 50° C. to about 80° C., preferably about 70° C., for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.

In reaction 3 of Preparation A, the compound of formula XIX is convertedto the corresponding compound of formula XVI by treating XIX withN-butyllithium, lithium diisopropylamine or sodium hydride, at atemperature of about −78° C., in the presence of a polar aproticsolvent, such as tetrahydrofuran. The anionic intermediate so formed isfurther reacted with (a) alkylhalide or benzylhalide, at a temperaturebetween about −78° C. to room temperature, preferably −78° C., when R³is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature betweenabout −78° C. to room temperature, preferably −78° C., when R³ isalkoxy; and (c) zinc chloride, at a temperature between about −78° C. toroom temperature, preferably −78° C., and the corresponding organozincintermediate so formed is then reacted with aryliodide or vinyl iodidein the presence of a catalytic quantity of palladium. The resultingreaction mixture is stirred at a temperature between about 50° C. toabout 80° C., preferably about 70° C., for a time period between about 1hour to about 3 hours, preferably about 1 hour. Alternatively, the anionso formed is reacted with molecular oxygen to form the corresponding4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI,wherein R³ is hydroxy.

In reaction 1 of Preparation B, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XXI is converted to the corresponding compound offormula XXII, according to the procedure described above in reaction 3of Preparation A.

In reaction 2 of Preparation B, the compound of formula XXII isconverted to the corresponding compound of formula XVI, according to theprocedures described above in reactions 1 and 2 of Preparation A.

In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compoundof formula XVII is converted to the corresponding compound of formulaXVI, wherein R is benzenesulfonyl or benzyl, by treating XVII withbenzenesulfonyl chloride, benzylchloride or benzylbromide in thepresence of a base, such as sodium hydride or potassium carbonate, and apolar aprotic solvent, such as dimethylformamide or tetrahydrofuran. Thereaction mixture is stirred at a temperature between about 0° C. toabout 70° C., preferably about 30° C., for a time period between about 1hour to about 3 hours, preferably about 2 hours.

In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compoundof formula XVI is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVIwith an amine of the formula HNR⁴R⁵. The reaction is carried out in analcohol solvent, such as tert-butanol, methanol or ethanol, or otherhigh boiling organic solvents, such as dimethylformamide, triethylamine,1,4-dioxane or 1,2-dichloroethane, at a temperature between about 60° C.to about 120° C., preferably about 80° C. Typical reaction times arebetween about 2 hours to about 48 hours, preferably about 16 hours. WhenR⁵ is a nitrogen containing heterocycloalkyl group, each nitrogen mustbe protected by a protecting group, such a benzyl. Removal of the R⁵protecting group is carried out under conditions appropriate for thatparticular protecting group in use which will not affect the Rprotecting group on the pyrrolo[2,3-d]pyrimidine ring. Removal of the R⁵protecting group, when benzyl, is carried out in an alcohol solvent,such as ethanol, in the present of hydrogen and a catalyst, such aspalladium hydroxide on carbon. The R⁵ nitrogen containinghetrocycloalkyl group so formed may be further reacted with a variety ofdifferent electrophiles of formula II. For urea formation, electrophilesof formula it such as isocyanates, carbamates and carbamoyl chloridesare reacted with the R⁵ nitrogen of the heteroalkyl group in a solvent,such as acetonitrile or dimethylformamide, in the presence of a base,such as sodium or potassium carbonate, at a temperature between about20° C. to about 100° C. for a time period between about 24 hours toabout 72 hours. For amide and sulfonamide formation, electrophiles offormula II, such as acylchlorides and sulfonyl chlorides, are reactedwith the R⁵ nitrogen of the heteroalkyl group in a solvent such asmethylene chloride in the presence of a base such as pyridine at ambienttemperatures for a time period between about 12 hours to about 24 hours.Amide formation may also be carried out by reacting a carboxylic acidwith the heteroalkyl group in the presence of a carbodiimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such asmethylene chloride at ambient temperatures for 12-24 hours. For alkylformation, electrophiles of formula II, such as α,β-unsaturated amides,acids, nitrites, esters, and α-halo amides, are reacted with the R⁵nitrogen of the heteroalkyl group in a solvent such as methanol atambient temperatures for a time period between about 12 hours to about18 hours. Alkyl formation may also be carried out by reacting aldehydeswith the heteroalkyl group in the presence of a reducing agent, such assodium cyanoborohydride, in a solvent, such as methanol, at ambienttemperature for a time period between about 12 hours to about 18 hours.

In reaction 3 of Scheme 1, removal of the protecting group from thecompound of formula XV, wherein R is benzenesulfonyl, to give thecorresponding compound of formula I, is carried out by treating XV withan alkali base, such as sodium hydroxide or potassium hydroxide, in analcohol solvent, such as methanol or ethanol, or mixed solvents, such asalcohol/tetrahydrofuran or alcohol/water. The reaction is carried out atroom temperature for a time period between about 15 minutes to about 1hour, preferably 30 minutes. Removal of the protecting group from thecompound of formula XV, wherein R is benzyl, is conducted by treating XVwith sodium in ammonia at a temperature of about −78° C. for a timeperiod between about 15 minutes to about 1 hour.

In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidine compoundof formula XX is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XXIV, according tothe procedure described above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 2, the 4-amino-5-halopyrrolo[2,3-d]pyrimidinecompound of formula XXIV, wherein R is benzenesulfonate and Z is bromineor iodine, is converted to the corresponding compound of formula XXIIIby reacting XXIV with (a) arylboronic acid, when R² is aryl, in anaprotic solvent, such tetrahydrofuran or dioxane, in the presence of acatalytic quantity of palladium (0) at a temperature between about 50°C. to about 100° C., preferably about 70° C., for a time period betweenabout 2 hours to about 48 hours, preferably about 12 hours; (b) alkynes,when R² is alkynyl, in the presence of a catalytic quantity of copper(I) iodide and palladium (0), and a polar solvent, such asdimethylformamide, at room temperature, for a time period between about1 hour to about 5 hours, preferably about 3 hours; and (c) alkenes orstyrenes, when R² is vinyl or styrenyl, in the presence of a catalyticquantity of palladium in dimethylformamide, dioxane or tetrahydrofuran,at a temperature between about 80° C. to about 100° C., preferably about100° C., for a time period between about 2 hours to about 48 hours,preferably about 48 hours.

In reaction 3 of Scheme 2, the compound of formula XXIII is converted tothe corresponding compound of formula XV, according to the proceduredescribed above in reaction 3 of Preparation A.

In reaction 1 of Scheme 3, the compound of formula XVII is converted tothe corresponding compound of formula I, according to the proceduredescribed above in reaction 2 of Scheme 1.

The compounds of the present invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as methanol orethanol. Upon careful evaporation of the solvent, the desired solid saltis readily obtained. The desired acid salt can also be precipitated froma solution of the free base in an organic solvent by adding to thesolution an appropriate mineral or organic acid.

Those compounds of the present invention that are acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform nontoxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g., magnesium stearate, talc orsilica); disintegrants (e.g., potato starch or sodium starch glycolate);or wetting agents (e.g., sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g., sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.,lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily estersor ethyl alcohol); and preservatives (e.g., methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use. The activecompounds of the invention may also be formulated in rectal-compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., asthma) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 0.1 mg to 1000 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

A compound of formula (I) administered in a pharmaceutically acceptableform either alone or in combination with one or more, additional agentswhich modulate a mammalian immune system or with antiinflammatoryagents, agents which may include but are not limited to cyclosporin A(e.g. Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus),leflunomide, deoxyspergualin, mycophenolate (e.g. Cellcept®,azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3 (e.g.Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone); and such agents may be administered as part of the sameor separate, dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg body weight, every12 hours, within first 48 hours postoperative. Does is monitored byserum Tacrolimus trough levels.

Cyclosporin A (Sandimmune oral or intravenous formulation, or Neoral®,oral solution or capsules) is given orally at 5 mg/kg body weight, every12 hours within 48 hours postoperative. Dose is monitored by bloodCyclosporin A trough levels.

The active agents can be formulated for sustained delivery according tomethods well known to those of ordinary skill in the art. Examples ofsuch formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598,4,173,626, 3,119,742, and 3,492,397.

The ability of the compounds of formula I or their pharmaceuticallyacceptable salts to inhibit Janus Kinase 3 and, consequently,demonstrate their effectiveness for treating disorders or conditionscharacterized by Janus Kinase 3 is shown by the following in vitro assaytests.

Biological Assay JAK3 (JH1:GST) Enzymatic Assay

The JAK3 kinase assay utilizes a protein expressed inbaculovirus-infected SF9 cells (a fusion protein of GST and thecatalytic domain of human JAK3) purified by affinity chromatography onglutathione-Sepaharose. The substrate for the reaction is poly-Glutamicacid-Tyrosine (PGT (4:1), Sigma catalog # P0275), coated onto Nunc MaxiSorp plates at 100 μg/ml overnight at 37° C. The morning after coating,the plates are washed three times and JAK3 is added to the wellscontaining 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24mM MgCl₂)+0.2 uM ATP+1 mM Na orthovanaidate.) The reaction proceeds for30 minutes at room temperature and the plates is washed three moretimes. The level of phosphorylated tyrosine in a given well isquantitated by standard ELISA assay utilizing an anti-phosphotyrosineantibody (ICN PY20, cat. #69-151-1).

Inhibition of Human IL-2 Dependent T-Cell Blast Proliferation

This screen measures the inhibitory effect of compounds on IL-2dependent T-Cell blast proliferation in vitro. Since signaling throughthe IL-2 receptor requires JAK-3, cell active inhibitors of JAK-3should, inhibit IL-2 dependent T-Cell blast proliferation.

The cells for this assay are isolated from fresh human blood. Afterseparation of the mononuclear cells using AccuspinSystem-Histopaque-1077 (Sigma # A7054), primary human T-Cells areisolated by negative selection using Lympho-Kwik T (One Lambda, Inc.,Cat # LK-50T). T-Cells are cultured at 1-2×10⁶/ml in Media (RPMI+10%heat-inactivated fetal calf serum (Hyclone Cat # A-1111-L)+1%Penicillin/Streptomycin (Gibco)) and induce to proliferate by theaddition of 10 ug/ml PHA (Murex Diagnostics, Cat # HA 16). After 3 daysat 37° C. in 5% CO₂, cells are washed 3 times in Media, resuspended to adensity of 1-2×10⁶ cells/ml in Media plus 100 Units/ml of humanrecombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the cells areIL-2 dependent and can be maintained for up to 3 weeks by feeding twiceweekly with equal volumes of Media+100 Units/ml of IL-2.

To assay for a test compounds ability to inhibit IL-2 dependent T-Cell;proliferation, IL-2 dependent cells are washed 3 times, resuspended inmedia and then plated (50,000 cells/well/0.1 ml) in a Flat-bottom96-well microtiter plate (Falcon # 353075). From a 10 mM stock of testcompound in DMSO, serial 2-fold dilutions of compound are added intriplicate wells starting at 10 uM. After one hour, 10 Units/ml of IL-2is added to each test well. Plates are then incubated at 37° C., 5% CO₂for 72 hours. Plates are then pulsed with ³H-thymidine (0.5 uCi/well)(NEN Cat # NET-027A), and incubated an additional 18 hours. Cultureplates are then harvested with a 96-well plate harvester and the amountof ³H-thymidine incorporated into proliferating cells is determined bycounting on a Packard Top Count scintillation counter. Data is analyzedby plotting the % inhibition of proliferation verses the concentrationof test compound. An IC₅₀ value (uM) is determined from this plot.

The following Examples illustrate the preparation of the compounds ofthe present invention but it is not limited to the details thereof.Melting points are uncorrected. NMR data are reported in parts permillion (δ) and are referenced to the deuterium lock signal from thesample solvent (deuteriochloroform unless otherwise specified).Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard5989®, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass). Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C.

EXAMPLE 11-{4-methyl-3-[methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanoneMethod A (1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine

To a stirred solution of 1-benzyl-4-methyl-piperidin-3-one (2.3 grams,11.5 mmol), prepared by the methods of lorio, M. A. and Damia, G.,Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the AmericanChemical Society, 107, 1768 (1985), (modified using 5% methanol as aco-solvent), both references are incorporated by reference in theirentirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran wasadded 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirredin a sealed tube for 16 hours at room temperature. Triacetoxy sodiumborohydride (4.9 grams, 23 mmol) was added and the new mixture stirredat room temperature in a sealed tube for 24 h, at which time, thereaction was quenched upon addition of 1 N sodium hydroxide (50 mL). Thereaction mixture was then extracted 3×80 mL with ether, the combinedether layers dried over sodium sulfate (Na₂SO₄) and concentrated todryness in vacuo affording 1.7 grams (69%) of the title compound as awhite solid. LRMS: 219.1 (M+1).

Method B(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

A solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9 mmol),prepared by the method of Davoll, J. Am. Chem. Soc., 82, 131 (1960),which is incorporated by reference in its entirety, and the product fromMethod A (1.7 grams, 7.95 mmol) dissolved in 2 equivalents oftriethylamine was heated in a sealed tube at 100° C. for 3 days.Following cooling to room temperature and concentration under reducedpressure, the residue was purified by flash chromatography (silica; 3%methanol in dichloromethane) affording 1.3 grams (50%) of the titlecompound as a colorless oil. LRMS: 336.1 (M+1).

Method CMethyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

To the product from Method B (0.7 grams, 2.19 mmol) dissolved in 15 mLof ethanol was added 1.5 mL of 2 N hydrochloric acid and the reactionmixture degassed by nitrogen purge. To the reaction mixture was thenadded 0.5 grams of 20% palladium hydroxide on carbon (50% water)(Aldrich) and the resulting mixture shaken (Parr-Shaker) under a 50 psiatmosphere of hydrogen at room temperature for 2 days. The Celitefiltered reaction mixture was concentrated to dryness in vacuo and theresidue purified by flash chromatography (silica; 5% methanol indichoromethane) affording 0.48 grams (90%) of the title compound. LRMS:246.1 (M+1).

Method D1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

To a stirred solution of the product from Method C (0.03 grams, 0.114mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added(0.018 grams, 0.28 mmol) of acetylchloride and the resulting mixturestirred at room temperature for 18 hours. The reaction mixture was thenpartitioned between dichloromethane and saturated sodium bicarbonate(NaHCO₃). The organic layer was washed again with saturated NaHCO₃,dried over sodium sulfate and concentrated to dryness in vacuo. Theresidue was purified by preparative thin layer chromatography (PTLC)(silica; 4% methanol in dichloromethane) affording 0.005 mg (15%) of thetitle compound as a colorless oil. LRMS: 288.1 (M+1).

The title compounds for examples 2-26 were prepared by a methodanalogous to that described in Example 1.

EXAMPLE 2[1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-amine. LRMS:353.

EXAMPLE 3(1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

(1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-amine. LRMS: 338.

EXAMPLE 4[1-Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[1-(Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-amine. LRMS: 366.

EXAMPLE 54-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid isobutyl ester

4-Methyl-3-methylamino-piperidine-1-carboxylic acid isobutyl ester.LRMS: 346.

EXAMPLE 6N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide

N-[2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)ethyl]-propionamide.LRMS: 409.

EXAMPLE 7(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-carbamicacid methyl ester

[2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]-carbamic acidmethyl ester. LRMS: 411.

EXAMPLE 8N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-isobutyramide

N-[2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl-isobutyramide.LRMS: 423.

EXAMPLE 9

(1-Methanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

(1-Methanesulfonyl-piperidin-3-yl)methyl-amine. LRMS: 310.

EXAMPLE 10(1-Ethanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

(1-Ethanesulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 324.

EXAMPLE 11Methyl-[1-(Propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

(1-Propylsulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 338.

EXAMPLE 12[1-(Butane-1-sulfonyl)-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

(1-Butylsulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 352.

EXAMPLE 132,2-Dimethyl-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide

2,2-Dimethyl-N-[2-(4-methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]-propionamide.LRMS: 437.

EXAMPLE 143-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrile

3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propionitrile. LRMS:313.

EXAMPLE 15(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester

[3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propyl]-carbamic addtert-butyl ester. LRMS: 417.

EXAMPLE 16Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-amine. LRMS:352.

EXAMPLE 17 3-Amino-1-{4-methyl-3-[methyl-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

3-Amino-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one. LRMS:317.

EXAMPLE 182-Methoxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

2-Methoxy-1-(4-methyl-3-methylamino-piperidin-1-yl)-ethanone. LRMS: 318.

EXAMPLE 192-Dimethylamino-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

2-Dimethylamino-1-(4-methyl-3-methylamino-piperidin-1-yl)-ethanone.LRMS: 331.

EXAMPLE 20(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester

[3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propyl]-carbamic acidtert-butyl ester. LRMS: 417.

EXAMPLE 213,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

3,3,3-Trifluoro-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one.

EXAMPLE 22N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-acetamide

N-[2-(4-Methyl-3-methylamino-piperidin-1-yl)-2-oxo-ethyl]-acetamide.LRMS: 345.

EXAMPLE 233-Ethoxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

3-Ethoxy-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one. LRMS:346.

EXAMPLE 244-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methylamide

4-Methyl-3-methylamino-piperidine-1-carboxylic acid methylamide. LRMS:303.

EXAMPLE 254-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid diethylamide

4-Methyl-3-methylamino-piperidine-1-carboxylic acid diethylamide. LRMS:345.

EXAMPLE 26Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]-amine.LRMS: 367.

1. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 2. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen; (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁸ is selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl R² and R³ areeach hydrogen.
 3. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 br 2; R⁴ selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁸ is independently selected from the group consisting ofhydrogen or (C₁-C₆)alkyl optionally substituted by deuterium, hydroxy,amino, trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₂-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 4. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkylamino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R²and R³ areeach hydrogen.
 5. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 6. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups are,optionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein d is 2; R⁹, R¹⁰, and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 7. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein d is 2; R⁹, R¹⁰, and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 8. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁸ is selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 9. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₂-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁸ is selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 10. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁶, R⁷, and R⁸ are each independently selected from the groupconsisting of hydrogen or (C₁-C₆)alkyl optionally substituted bydeuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 11. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein X is S(O)_(n) wherein n is 0, 1 or 2; R⁹ and R¹⁰ are eachindependently selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 12. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein X is S(O)_(n) wherein n is 0, 1 or 2; R⁹, R¹⁰ and R¹¹ are eachindependently selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 13. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₂-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁹, R¹⁰ and R¹¹ are each independently selected from the groupconsisting of hydrogen or (C₁-C₆)alkyl optionally substituted bydeuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 14. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen or (C₁-C₆)alkyl optionally substituted bydeuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 15. A compound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein Y is S(O)_(n) wherein n is 0, 1 or 2; R⁸, R⁹, and R¹⁰ are eachindependently selected from the group consisting of hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkylwherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ are each independently selectedfrom hydrogen or (C₁-C₆)alkyl; R² and R³ are each hydrogen.
 16. Acompound of the Formula I;

or a pharmaceutically acceptable salt thereof; wherein R¹ is a group ofthe formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is a piperidinyl substituted by one to fivecarboxy, cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R¹⁵R¹⁶NS (O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl,R¹⁵S(O)_(m)R¹⁶N, R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 andR¹⁵ and R¹⁶ are each independently selected from hydrogen or(C₁-C₆)alkyl; or a group of the formula

wherein R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from thegroup consisting of hydrogen or (C₁-C₆)alkyl optionally substituted bydeuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)acylamino, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acylamino, amino(C₁-C₆)acyl,amino(C₁-C₆)acyl(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl,R¹⁵C(O)NH, R¹⁵OC(O)NH, R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl, R¹⁵R¹⁶NS(O)_(m),R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach hydrogen.
 17. A compound selected from the group consisting of:({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-aceticacid ethyl ester;N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-N′-propyl-piperidine-1-carboxamidine;andN-cyano-4,N′,N′-Trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxamidine,or a pharmaceutically acceptable salt thereof.
 18. A compound selectedfrom the group consisting of:1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone;[1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;(1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;[1-(Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid isobutyl ester;N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide;(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-carbamicacid methyl ester;N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-isobutyramide;(1-Methanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;(1-Ethanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;Methyl-[1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;[1-(Butane-1-sulfonyl)-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;2,2-Dimethyl-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide;(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester;3-Amino-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;2-Methoxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone;2-Dimethylamino-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone;(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester;N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-acetamide;3-Ethoxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methylamide;4-Methyl-3-4methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid diethylamide;Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine,or a pharmaceutically acceptable salt thereof.